Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
  • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
  • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

• This invention relates to pharmaceutical compositions and uses, in particular to pharmaceutical compositions comprising zoledronic acid or salts or hydrates thereof and to new therapeutic uses of zoledronic acid or salts or hydrates thereof.
• Bisphosphonates are analogues of pyrophosphate and exhibit marked effects on bone metabolism.
• the bisphosphonates' characteristic phosphorus-carbon-phosphorus bond (P-C-P) renders the class resistant to hydrolysis by phosphatases and enables these molecules to bind tightly to calcified bone matrix. They are very effective inhibitors of osteoclastic bone resorption and have been used clinically in Paget's disease of bone, osteoporosis, hypercalcemia of malignancy and bone metastases.
• Zoledronic acid i.e.1- hydroxy-2-(imidazol-1-yl)ethane-1 ,1-diphosphonic acid, is a nitrogen containing bisphosphonate (third generation).
• zoledronic acid has demonstrated inhibition of bone resorption in vitro at concentrations of 0.3-30 nM, and in vivo at doses of 0.3-30 ⁇ g/kg without exerting any untoward effects on either bone formation or mineralization.
• Hip fractures are the most devastating of the osteoporotic fractures. Patients with hip fractures lose bone mass and muscle mass in the year following the fracture. There is a very high risk of subsequent fractures after hip fracture in both men and women. These secondary fractures significantly impact the quality of life of patients already struggling to recover from their initial hip fracture. Men and women hip fracture patients have much to gain from the development of an effective secondary fracture prevention intervention. It has now been found that administration of a zoledronic acid or salts or hydrates thereof to a patient who has recently undergone surgical repair of a hip fracture, significantly reduces the rate of all subsequent osteoporotic skeletal fractures.
• the present invention provides a method for the treatment of osteoporosis post-hip fracture to prevent or reduce subsequent osteoporotic skeletal fractures in a patient in need of such treatment, which method comprises administering an effective amount of a bisphosphonate to said patient, particularly to a patient who has recently undergone surgical repair of the hip fracture.
• the invention further provides use of a bisphosphonate in the preparation of a medicament for the treatment of osteoporosis post hip fracture to prevent or reduce subsequent osteoporotic skeletal fractures in a patient in need of such treatment, and particularly to a patient who has undergone recent repair of the hip fracture.
• the present invention is particularly applicable to the patients who have had a hip fracture repair within the past three months, e.g., the past 90 days, past 60 days, the past 5-45 days, the past 1-42 days, past 7-42 days or past 1-7 days, preferably wherein the hip fracture repair was within the past 90 days.
• the methods of the present invention represent an improvement to existing therapy of patients who have undergone a hip fracture in which zoledronic acid is used to prevent or curtail the occurrence of any subsequent osteoporotic skeletal fractures.
• treatment or "treat” refer to preventative treatment.
• Zoledronic acid is intended to include the free acid itself, i.e., 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, as well as any pharmaceutically acceptable salts and hydrates thereof and solvates thereof forming from other solvents used for its crystallization.
• 1-hydroxy-2-(imidazol-1-yl)ethane-1 ,1-diphosphonic acid and its pharmacologically acceptable salts, hydrates and solvates are well-known from the literature. They can be prepared by procedures known in the art, such as described, e.g., in U.S. Patent No. 4,939,130. See also U.S. Patent Nos. 4,777,163 and 4,687,767. The contents of the latter three patents are hereby incorporated by reference in their entirety.
• Pharmacologically acceptable salts are preferably salts with bases, conveniently metal salts derived from Groups la, lb, lla and lib of the Periodic Table of the Elements, including alkali metal salts, e.g., potassium and especially sodium salts, or alkaline earth metal salts, preferably calcium or magnesium salts, and also ammonium salts with ammonia or organic amines.
• bases conveniently metal salts derived from Groups la, lb, lla and lib of the Periodic Table of the Elements, including alkali metal salts, e.g., potassium and especially sodium salts, or alkaline earth metal salts, preferably calcium or magnesium salts, and also ammonium salts with ammonia or organic amines.
• Especially preferred pharmaceutically acceptable salts are those where one, two, three or four, in particular one or two, of the acidic hydrogens of the zoledronic acid are replaced by a pharmaceutically acceptable cation, in particular sodium, potassium or ammonium, in the first instance sodium.
• a very preferred group of pharmaceutically acceptable salts is characterized by having one acidic hydrogen and one pharmaceutically acceptable cation, especially sodium, in each of the phosphonic acid groups.
• Zoledronic acid is preferably used in the form of pharmaceutical compositions that contain a therapeutically effective amount of zoledronic acid active ingredient optionally together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for administration.
• compositions for enteral such as oral, rectal, aerosol inhalation or nasal administration
• compositions for parenteral such as intravenous or subcutaneous administration
• compositions for transdermal administration e.g., passive or iontophoretic.
• the pharmaceutical compositions are adapted to oral or parenteral (especially intravenous, intra-arterial or transdermal) administration.
• Intravenous and oral, first and foremost intravenous, administration is considered to be of particular importance.
• the zoledronic acid active ingredient is in the form of a parenteral, most preferably an intravenous form.
• the particular mode of administration and the dosage may be selected by the attending physician taking into account the particulars of the patient, especially age, weight, life style, activity level, hormonal status, e.g., post-menopausal, and bone mineral density as appropriate.
• the zoledronic acid is administered intravenously.
• the dosage of the zoledronic acid may depend on various factors, mode of administration, warm-blooded species, and/or sex, age, weight and individual condition of the warm-blooded animal.
• the dosage is such that a single dose of zoledronic acid or salt or hydrate thereof from 0.002-20.0 mg/kg, especially 0.01-10.0 mg/kg, is administered to a warmblooded animal weighing approximately 75 kg. If desired, this dose may also be taken in several, optionally equal, partial doses. Doses of zoledronic acid or salts or hydrates thereof in the range from about 0.5 mg to about 20 mg, preferably from about 1 mg to about 10 mg, more preferably 5 mg, may be used for treatment of human patients.
• the 5 mg dose is generally administered over a 15-minute period although shorter and longer periods are possible.
• mg/kg means mg drug per kg body weight of the mammal - including man - to be treated.
• the zoledronic acid is doses at intervals of at least about once every six months, e.g., once every 180 days, or less frequently, conveniently once a year, or at any interval in between, e.g., once every 7, 8, 9, 10 or 11 months, such as disclosed in co-pending International Patent Application WO 01/97788, the contents of which are herein incorporated by reference.
• Dosing intervals of greater than once per year may be used, e.g., about once every 18 months or about once every 2 years, or even less frequently, e.g., a frequency of up to about once every 3 years or less often.
• the dose mentioned above is preferably administered once per year (understanding, of course, that it may not be exactly one year to date but rather at yearly check-ups).
• Formulations in single dose unit form contain preferably from about 1% to about 90%, and formulations not in single dose unit form contain preferably from about 0.1% to about 20%, of the zoledronic acid active ingredient.
• Single dose unit forms, such as capsules, tablets or dragees contain, e.g., from about 1 mg to about 500 mg of the zoledronic acid active ingredient.
• compositions for enteral and parenteral administration are, for example, those in dosage unit forms, such as dragees, tablets or capsules and also ampoules. They are prepared in a manner known per se, for example, by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes.
• compositions for oral administration can be obtained by combining the active ingredient with solid carriers, where appropriate granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, into tablets or dragee cores.
• Suitable carriers are especially fillers, such as sugars, for example, lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross- linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
• fillers such as sugars, for example, lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate
• binders such as starch pastes
• Adjuncts are especially flow-regulating agents and lubricants, for example, silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
• Dragee cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions that optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures or, to produce coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Coloring substances or pigments may be added to the tablets or dragee coatings, for example for the purpose of identification or to indicate different doses of active ingredient.
• dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the dry-filled capsules may contain the active ingredient in the form of a granulate, for example, in admixture with fillers, such as lactose; binders, such as starches; and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilizers.
• the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers to be added.
• Parenteral formulations are especially injectable fluids that are effective in various manners, such as intra-arterially, intramuscularly, intraperitoneally, intranasally, intradermally, subcutaneously or preferably intravenously.
• Such fluids are preferably isotonic aqueous solutions or suspensions which can be prepared before use, for example, from lyophilized preparations which contain the active ingredient alone or together with a pharmaceutically acceptable carrier.
• the pharmaceutical preparations may be sterilized and/or contain adjuncts, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers.
• transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the active ingredient of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
• Example 1 Preparation of Capsules Containing Coated Pellets of Active Ingredient Core pellet:
• a mixture of active ingredient with Avicel PH 105 is moistened with water and kneaded, extruded and formed into spheres.
• the dried pellets are then successively coated in the fluidized bed with an inner coating, consisting of cellulose HP-M 603, polyethylene glycol (PEG) 8000 and talc, and the aqueous gastric juice-resistant coat, consisting of Eudragit ® L 30 D, triethyl citrate and Antifoam ® AF.
• the coated pellets are powdered with talc and filled into capsules (capsule size 0) by means of a commercial capsule filling machine, for example, Hofliger and Karg.
• Example 2 Monolith Adhesive Transdermal System Containing 1-hydroxy-2-(imidazol-1-vQ- ethane-1 ,1-diphosphonic acid (zoledronic acid)
• the above components are together dissolved in 150 g of special boiling point petroleum fraction 100-125 by rolling on a roller gear bed.
• the solution is applied to a polyester film (Hostaphan, Kalle) by means of a spreading device using a 300 mm doctor blade, giving a coating of about 75 g/m 2 .
• a silicone- treated polyester film Thickness 75 mm, Laufenberg
• the finished systems are punched out in sizes in the wanted form of from 5-30 cm 2 using a punching tool.
• the complete systems are sealed individually in sachets of aluminized paper.
• Example 3 Vial Containing 1.0 m ⁇ Drv. Lvophilized 1-hvdroxy-2-(imidazol-1-yl)ethane-1.1- diphosphonic acid (mixed sodium salts thereof)
• the active ingredient is titrated with trisodium citrate x 2 H 2 O to pH 6.0. Then, the mannitol is added and the solution is lvophilized and the lyophilisate filled into a vial.
• the solution (concentration 3 mg/mL) is for i.v. infusion after dilution.
• zoledronic acid is used in the form of the free acid.
• the primary objective is to demonstrate, that zoledronic acid, administered annually (5 mg i.v. over 15 minutes) plus a loading dose of 75,000 - 125,000 units of vitamin D2 IM or orally once or 50,000 - 75,000 units of vitamin D3 IM or orally once and a maintenance dose of 800 - 1200 IU of vitamin D p.o. daily and elemental calcium (1000 - 1500 mg p.o.
• BMD Bone Mineral Density
• DXA dual X-ray absorptiometry
• Total hip BMD and femoral neck BMD will be collected by DXA at each investigator site and reported on CRF page at randomization visit and every 12 month visit thereafter. Percentage change from baseline of total hip BMD and femoral neck BMD will be computed for each of those patients, and used for the analysis.
• All patients signing informed consent at screening will receive a loading dose of 75,000 - 125,000 units of vitamin D2 or 50,000 - 75,000 units of vitamin D3 IM or orally and then begin a maintenance dose of 800 - 1200 IU of vitamin D p.o daily and elemental calcium (1000 - 1500 mg p.o. daily in a divided dose).
• Subjects will continue their daily maintenance dose of 800 - 1200 IU of vitamin D and elemental calcium (1000 - 1500 mg p.o. daily in a divided dose) at least 14 days prior to receiving study drug (zoledronic acid 5 mg IV over 15 minutes or placebo).
• Subjects may receive their study drug infusion at any time between day 14 post vitamin D2 or D3 administration and 90 days after surgical repair of their low trauma hip fracture.
• a 25-OH vitamin D level result must be available and greater than or equal to 15 ng/ml, so the patient can be dosed.
• the patients will receive study drug (zoledronic acid 5 mg IV over 15 minutes or placebo) every 12 months until 211 patients have reached the primary endpoint.
• the study drug will be prepared at the site and zoledronic acid or placebo will be dispensed according to randomization received through an Interactive Voice Response System (IVRS).
• IVRS Interactive Voice Response System
• the Steering Committee though blinded to treatment group, may recommend changing target enrollment or extending follow- up time based on the event rate observed during interim event rate analyses. Approximately 115 sites will be recruited: approximately 40 in the United States, approximately 10 in Canada, and approximately 65 in the rest of the world to enroll approximately 1714 patients which are estimated to achieve 211 clinical fracture events.
• Hip BMD will be measured using dual X-ray absorptiometry (DXA) of the non-fracture hip at randomization and every 12 months during the study. If the site is unable to measure hip BMD of non-fracture hip then a lumbar spine BMD will be measured for safety only.
• DXA dual X-ray absorptiometry
• Concomitant medications and co-morbid illnesses will be recorded at each study visit and vital signs will be measured at randomization. Height and weight will be measured at, randomization, 12 months and every annual visit, thereafter. A chemistry panel will be measured at randomization, 12 months and every 12 months, thereafter. Calculated creatinine clearance will also be determined within 4 weeks of randomization, 12 month visit and every 12 months, thereafter. The calculated creatinine clearance must be known within 4 weeks prior to giving study drug to the patient. A CBC will be performed at visit 1 for baseline safety assessment of eligibility. Chest and hip X-rays will be collected at screening. Hip X-ray of the incident hip will be performed at 6 months. Hip fracture healing will be assessed using clinical signs and symptom (persistent pain and/or inability to bear weight on index hip) at randomization, 6 and 12 months following the index fracture repair. All subjects reporting these signs or symptoms will have hip radiographs reviewed by the CEC.
• the study population will consist of men and women aged 50 years and older who. have suffered a recent low-trauma, acute hip fracture and were ambulatory prior to the fracture. Patients admitted to orthopedic surgical or medical services, extended care or rehabilitation facilities and seen in clinic will be identified. Eligible patients will be ascertained from hospital admission logs, or operating room logs, extended care facility/rehabilitation logs and clinic schedules. At this time, the purpose of the study will be explained to the patient and, if necessary, their surrogates. If the patient/surrogate agrees to participate, the informed consent form will be signed and a chemistry panel, calculated creatinine clearance and a CBC will be performed. Patients will be instructed to take the vitamin D loading dose, vitamin D and elemental calcium supplements daily.
• CAM Confusion Assessment method
• Those patients judged to lack capacity for informed consent by study personnel or clinical staff will be given a brief explanation of the study and asked for assent. If this is given, full informed consent will be sought from the patient's legally authorized representative.
• the legal representative will be determined according to the state or national laws governing the study site and in accordance with ICH guidelines.
• Patient may be randomized up to 90 days post-surgical repair of a low-trauma hip fracture
• Serum calcium greater than 2.75 mmoL/L (11.0 mg/dL) 7. Serum alkaline phosphatase, greater than 2.5 X ULN
• DCIS Ductal Carcinoma in-situ
• CIS Carcinoma in-situ
• wash out period for PTH and PTH analogs is 6 months.
• the reference point for the washout period should be the date of randomization
• Hip fractures unlikely to be due to osteoporosis traumatic fracture, malignant fracture, osteomyelitic fracture, hardware related fracture
• the IVRS must also be called and the patient's discontinuation reported accordingly.
• Zoledronic acid or placebo (5.0 mg) will be administered within 90 days of surgical repair of hip fracture, at the 12 month study visit and annually until the study is completed, as a result of the required number of fractures have occurred and have been adjudicated.
• Zoledronic acid or placebo (physiologic 0.9% normal saline) is to be given intravenously to each patient as a slow infusion over 15 minutes.
• a patient's supply of vitamin D and elemental calcium will be provided to satisfy the patient's requirement until the next scheduled visit.
• Patient specific double blinded drug kits will be prepared by Clinical Trial Services (CTS). Active drug kits will contain vials of zoledronic acid (5 mg in 5 ml of sterile water for injection) and 2 (10mL) physiologic (0.9%) normal saline for the flushing of the intravenous line. Placebo kits will contain identical placebo vials (excipients in 5 ml of sterile water) and 2 (10mL) physiologic (0.9%) normal saline for the flushing of the intravenous line. Bulk supplies of physiologic (0.9%) normal saline for a diluted total injection volume of 105 ml will be sent only to clinical sites in the United States and Canada, other countries will use their own supply.
• CTS Clinical Trial Services
• the study drug will be stored at room temperature in a locked area at each center until they are returned to Novartis or its designee at the end of the study.
• Diluted zoledronic acid infusion solutions are stable for at least 24 hours at 2-8°C.
• the cumulative time between dilution with infusion media, storage in a refrigerator and end of administration must not be longer than 24 hours.
• diluted zoledronic acid solutions should be used immediately. However, if diluted zoledronic acid solutions cannot be used immediately, the solutions must be refrigerated at temperatures between 2-8°C. Before administration, the solution should be allowed to slowly warm to room temperature again.
• the study-drug solutions should be prepared in plastic syringes and tubings (polyvinylchloride, polyethtylene or polypropylene) and infused from a plastic bag or a glass bottle.
• Zoledronic acid or placebo is to be given intravenously to each patient as a slow infusion over 15 minutes.
• the appropriate volume of zoledronic acid is to be mixed with an appropriate volume of physiologic (0.9%) normal saline so that the total volume of infused solution is 105 ml.
• Clinically evident fractures occurring in the follow-up period are the primary endpoint. Facial, skull and digital fractures are not associated with osteoporosis and will not qualify as an outcome.
• the site study coordinator will obtain copies of radiology reports or physician's chart documentation of X-ray results for non-vertebral fractures. These will be submitted to the Clinical Endpoint Committee (CEC) within 1 week of the patient's report of the event. Radiographs will also be requested for some fractures that require further confirmation.
• CEC Clinical Endpoint Committee
• the diagnosis of clinically evident vertebral fracture will require the following: 1) acute onset or worsening back pain in a localized area of the spine as triggered in the CRF, and 2) PA and lateral lumbar spine films (obtained during routine clinical care) showing one or more grade of vertebral height loss by the semi-quantitative technique of Genant et al in comparison with baseline X-rays.
• a modification of the Genant criteria will be used in order to improve specificity for vertebral fracture.
• an incident fracture will be defined as one or more vertebrae with grade 2 or higher deformity. If modalities other than plain film are used to diagnose the vertebral fracture, an incident fracture is defined as a significant deformity in a vertebrae with no greater than grade 1 deformity at baseline.
• hip If a patient suffers more than one fracture after hip fracture, the first such event will be counted as the primary endpoint. If a patient suffers more than one fracture at the same time, the most clinically serious will be counted as the primary endpoint in the following hierarchy: hip, long bone, vertebral, wrist, other.
• BMD Bone Mineral Density
• DXA dual X-ray absorptiometry
• Total hip BMD and femoral neck BMD will be measured by DXA at each investigator site and reported on CRF page at randomization visit and every 12 month visit thereafter. Percentage change from baseline of total hip BMD and femoral neck BMD will be computed for each of those patients, and used for the analysis.
• the study is designed to show superiority of zoledronic acid compared to placebo in reducing clinical fracture rate after surgical repair of low-trauma hip fracture.
• the primary endpoint is "time to event" (time from randomization to first clinical fracture), and log-rank test will be used in the primary analysis.
• the primary analysis population is intent-to-treat. This trial will continue until 211 patients reached primary endpoint.
• the specifications described are those envisaged at the time of planning the trial.
• ITT Intent-to-treat population
• Intent-to-treat analysis data set will include all randomized subjects.
• Per-protocol analysis data set will include all subjects without any major protocol violation. The protocol violations will be identified before unblinding.
• Summary statistics for background and demographic variables will be provided by treatment groups.
• the randomization comparability between treatment groups will be evaluated for the background and demographic variables.
• Categorical variables will be evaluated using Fisher's exact test, and the continuous variables will be evaluated using a one-way analysis of variance model.
• the analysis of primary efficacy variable will be performed on the intent-to-treat and per- protocol populations.
• the primary analysis population is intent-to-treat population.
• the analysis of secondary efficacy variables will be performed on intent-to-treat population. In addition, adjustment for multiple comparisons will not be made for any of the secondary efficacy variables.
• the primary efficacy endpoint is time to first clinical fracture. Between-treatment differences will be evaluated using a log-rank test to compare the time to clinical fracture between the two treatment groups. The Kaplan-Meier estimates of the time to clinical fracture for each treatment will be plotted. The Kaplan-Meier estimates of incidence of clinical fractures at the end of study will be presented.
• the censoring time will be computed from the date of first infusion to the date of the last study visit.
• centers/countries will be pooled into regions to assess any geographical differences that may exist between treatments.
• a pooling scheme will be decided before unblinding. Tabular and/or graphical methods will be used to assess treatment-by-region interaction as appropriate (secondary analysis on primary endpoint).
• the secondary efficacy endpoints are the percent change relative to randomization of total hip BMD and femoral neck BMD at month 12, 24 and every 12 months thereafter. Percent change from randomization at each visit will be analyzed for BMD efficacy variables. Between-treatment differences will be evaluated using a two-way analysis of variance (ANOVA) model with treatment and center as explanatory variables.
• ANOVA analysis of variance
• a positive outcome is indicated by both the 12-month and 24-month results showing a significant reduction in secondary osteoporotic fractures in patients who have recently undergone surgical repair of a hip fracture when they take zoledronic acid once per year in combination with vitamin D and calcium therapy vs. those patients taking vitamin D and calcium therapy alone.

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